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Synthesis and Biological Evaluation of N-Aryl-5-aryloxazol-2-amine Derivatives as 5-Lipoxygenase Inhibitors.

Chemical & pharmaceutical bulletin (2015-06-05)
Jee Hee Suh, Eul Kgun Yum, Young Sik Cho
ABSTRACT

We describe the synthesis and biological evaluation of N-aryl-5-aryloxazol-2-amine derivatives that are able to inhibit 5-lipoxygenase (5-LOX), a key enzyme of leukotriene synthesis, for the treatment of inflammation-related diseases including asthma and rheumatoid arthritis. A novel structural moiety containing oxazole was initially identified from a chemical library using an in vitro enzymatic and cell-based assay, and its synthesized oxazole derivatives were further examined to develop a structure-activity relationship (SAR). SAR analysis demonstrated that a hydroxyl or amino group at the p-position on N-phenyl was essential for the 5-LOX-inhibitory activities of the derivatives, and that other halogen and methyl group-substituted derivatives affected the potency, positively or negatively. As a result, derivatives selected through first-round screening were further optimized using a cell-based assay and an in vivo assay to develop a potent, selective 5-LOX inhibitor. A final hit exhibited an improved efficacy in arachidonic acid-induced ear edema when applied topically but not orally. Moreover, it showed the additional advantage of sustainable antiinflammatory activity over a reference compound, zileuton. Taken together, chemical entities bearing an oxazole scaffold could be promising as therapeutic drugs for the treatment of chronic inflammatory skin disorders.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Dimethyl sulfoxide-d6, 99.9 atom % D
Sigma-Aldrich
Hexadecyltrimethylammonium bromide, ≥98%
Sigma-Aldrich
Dimethyl sulfoxide-d6, 99.9 atom % D, contains 0.03 % (v/v) TMS
Sigma-Aldrich
Hexadecyltrimethylammonium bromide, for molecular biology, ≥99%
Sigma-Aldrich
Dimethyl sulfoxide-d6, "100%", 99.96 atom % D
Sigma-Aldrich
Dimethyl sulfoxide-d6, 99.5 atom % D
Sigma-Aldrich
Hexadecyltrimethylammonium bromide, BioXtra, ≥99%
Sigma-Aldrich
Arachidonic acid, >95.0% (GC)
Sigma-Aldrich
Arachidonic acid, from non-animal source, ≥98.5% (GC)
Sigma-Aldrich
Hexadecyltrimethylammonium bromide, BioUltra, for molecular biology, ≥99.0% (AT)
Sigma-Aldrich
Dimethyl sulfoxide-d6, "100%", 99.96 atom % D, contains 0.03 % (v/v) TMS
Sigma-Aldrich
Dimethyl sulfoxide-d6, 99.9 atom % D, contains 1 % (v/v) TMS
Sigma-Aldrich
Dimethyl sulfoxide-d6, anhydrous, 99.9 atom % D
Sigma-Aldrich
Dimethyl sulfoxide-d6, "Special HOH", ≥99.9 atom % D
Sigma-Aldrich
2,3-Dimethylphenol, 98%
Sigma-Aldrich
Dimethyl sulfoxide-d6, "100%", 99.96 atom % D
SAFC
Hexadecyltrimethylammonium bromide
Sigma-Aldrich
Dimethyl sulfoxide-d6, "100%", 99.96 atom % D